Melatonin attenuates ferroptosis-associated injury through modulation of the thioredoxin-interacting protein/thioredoxin-1/glutathione peroxidase 4 pathway after neonatal hypoxic ischemic brain damage.
TL;DR
Mel attenuates acute neonatal HIBD and reduces ferroptosis-associated neuronal injury, potentially involving modulation of the TXNIP/Trx-1/GPX4 pathway.
Abstract
Objective
This study aimed to elucidate the neuroprotective mechanism of melatonin (Mel) against hypoxic-ischemic brain damage (HIBD) in neonatal rats, specifically through the thioredoxin-interacting protein (TXNIP)/thioredoxin-1 (Trx-1)/glutathione peroxidase 4 (GPX4) pathway in neuronal ferroptosis, and to concurrently evaluate its therapeutic efficacy using multimodal MRI.
Methods
A neonatal rat HIBD model was established with pre- and postmodeling Mel administration. Neuroprotective effects were dynamically assessed in vivo via multimodal MRI. Hippocampal tissues were analyzed for ferroptosis markers and pathway components. In vitro, PC12 cells underwent oxygen-glucose deprivation (OGD) with or without Mel. TXNIP-overexpressing cells were used to verify the axis's specific role.
Results
MRI confirmed that Mel significantly reduced infarct volume and improved cerebral blood flow (all P < 0.05). It preserved neuronal and mitochondrial integrity. Molecularly, Mel restored GPX4/Trx-1 and suppressed acyl-CoA synthetase long-chain family member 4/TXNIP (all P < 0.05). These effects were replicated in OGD-PC12 cells and persisted in TXNIP-overexpressing cells, supporting the involvement of this pathway.
Conclusion
Mel attenuates acute neonatal HIBD and reduces ferroptosis-associated neuronal injury, potentially involving modulation of the TXNIP/Trx-1/GPX4 pathway. Multimodal MRI may serve as a useful in-vivo tool for evaluating therapeutic responses after neonatal HIBD.